Testicular Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Testicular Cancer Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of testicular cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: A separate PDQ summary on Testicular Cancer Screening is also available.

Note: Estimated new cases and deaths from testicular cancer in the United States in 2009:[1]

  • New cases: 8,400.
  • Deaths: 380.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Testicular cancer is a highly treatable, often curable, cancer that usually develops in young and middle-aged men. Testicular cancer is broadly divided into seminoma and nonseminoma types for treatment planning because seminomas are more sensitive to radiation therapy. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage disease, the cure rate approaches 100%.[2,3]

Tumors that have a mixture of seminoma and nonseminoma components should be managed as nonseminomas. Nonseminomas include embryonal carcinomas, teratomas, yolk sac carcinomas, choriocarcinomas, and various combinations of these cell types. Tumors that appear to have a seminoma histology but that have elevated serum levels of alpha-fetoprotein (AFP) should be treated as nonseminomas. Elevation of the beta subunit of human chorionic gonadotropin (hCG) alone is found in approximately 10% of the patients with pure seminoma.

Risk of metastases is lowest for teratoma and highest for choriocarcinoma, with the other cell types having intermediate risk.

A number of prognostic classification schema are in use for metastatic nonseminomatous testicular cancer and for primary extragonadal nonseminomatous germ cell cancers treated with chemotherapy.[4,5,6] Most incorporate some or all of the following factors, which may independently predict worse prognosis:

  • Presence of liver, bone, or brain metastases.
  • Very high serum markers.
  • Primary mediastinal nonseminoma.
  • Large number of lung metastases.

Even patients with widespread metastases at presentation, including those with brain metastases, may be curable and should be treated with this intent.[7]

Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice in treating a malignant testicular mass.[8] Transscrotal biopsy is not considered appropriate because of the risk of local dissemination of tumor into the scrotum or its spread to inguinal lymph nodes. A retrospective analysis of reported series in which transscrotal approaches had been used showed a small but statistically significant increase in local recurrence rates compared with the recurrence rates when the inguinal approach was used (2.9% vs. 0.4%).[9][Level of evidence: 3iiiDii] Distant recurrence and survival rates, however, were indistinguishable in the two approaches. Local recurrence was similar in patients who did not have scrotal violation, regardless of whether or not additional treatments, such as hemiscrotal radiation therapy, hemiscrotal resection, or inguinal lymph node dissection, were used.

An important aspect of the diagnosis and follow-up of testicular cancer is the use of serum markers. Serum markers include AFP, hCG (measurement of the beta subunit reduces luteinizing hormone cross-reactivity), and lactate dehydrogenase. The serum markers may detect a tumor that is too small to be discovered on physical examination or x-rays. In patients younger than 15 years, approximately 90% of testicular germ cell cancers are yolk sac tumors. In these types of patients, the AFP is elevated at diagnosis and is an excellent indicator of response to therapy and disease status.[10] Serum markers plus chest x-rays are important parts of the monthly checkups for patients after definitive therapy of testicular cancer as well as periodic abdominal computed tomographic (CT) scans for 2 to 3 years. The absence of markers does not mean the absence of tumor. After diagnosis and treatment, patients typically receive follow-up monthly for the first year and every other month for the second year. While the majority of tumor recurrences appear within 2 years, late relapse has been reported, and lifelong marker, radiologic, and physical examination is recommended.[11]

Evaluation of the retroperitoneal lymph nodes, usually by CT scanning, is an important aspect of treatment planning in adults with testicular cancer.[12,13] Patients with a negative result however, have a 25% to 30% chance of having microscopic involvement of the lymph nodes. For seminoma, some physicians think that knowing the results of both the lymphangiogram and the CT scan is important for treatment planning. For nonseminoma, the inaccuracy of both is a problem, and frequently surgical staging is required. About 25% of patients with clinical stage I nonseminomatous testicular cancer will be upstaged to pathologic stage II with retroperitoneal lymph node dissection (RPLND), and about 25% of clinical stage II patients will be downstaged to pathologic stage I with RPLND.[14] In children, the use of serial measurements of AFP has proven sufficient for monitoring response after initial orchiectomy. Lymphangiography and para-aortic lymph node dissection do not appear to be useful or necessary in the proper staging and management of these patients.[10]

Patients who have been cured of testicular cancer have approximately a 2% to 5% cumulative risk of developing a cancer in the opposite testicle during the 25 years after initial diagnosis.[15,16,17] Within this range, men with nonseminomatous primary tumors appear to have a lower risk of subsequent contralateral testis tumors than men with seminomas.[17,18]

HIV-infected men are reported to be at increased risk for developing testicular germ cell cancer.[19] Depending on comorbid conditions such as active infection, these men are generally managed similarly to non-HIV-infected patients.

Because the majority of testis cancer patients who receive chemotherapy are curable, it is necessary to be aware of possible long-term effects of platinum-based treatment, such as the following:

1. Fertility: Many patients have oligospermia or sperm abnormalities prior to therapy. Virtually all become oligospermic during chemotherapy. Many recover sperm production, however, and can father children, often without the use of cryopreserved semen. In a population-based study,70% of patients actually fathered children.[20] The likelihood of recovering fertility is related to the type of treatment received. The children do not appear to have an increased risk of congenital malformations.[21,22,23,24]
2. Secondary leukemias: Several reports of elevated risk of secondary acute leukemia, primarily nonlymphocytic, have appeared.[25] In some cases, the risks were associated with the prolonged use of alkylating agents or with the use of radiation.[26,27] Etoposide-containing regimens are also associated with a risk of secondary acute leukemias, usually in the myeloid lineage, and with a characteristic 11q23 translocation.[25,28,29,30] Etoposide-associated leukemias typically occur sooner after therapy than alkylating agent-associated leukemias and often show balanced chromosomal translocations on the long arm of chromosome 11.[25] Standard etoposide dosages (<2 g/m2 cumulative dose) are associated with a relative risk of 15 to 25, but this translates into a cumulative incidence of leukemia of less than 0.5% at 5 years. Preliminary data suggest that cumulative doses of more than 2 g/m2 of etoposide may confer higher risk.
3. Renal function: Minor decreases in creatinine clearance occur (about a 15% decrease, on average) during platinum-based therapy, but these appear to remain stable in the long term and without significant deterioration.[31]
4. Hearing: Bilateral hearing deficits occur with cisplatin-based chemotherapy, but the deficits generally occur at sound frequencies of 4 kHz to 8 kHz, which is outside the range of conversational tones;[31] therefore, hearing aids are rarely required if standard doses of cisplatin are administered.

Although bleomycin pulmonary toxic effects may occur, it is rarely fatal at total cumulative doses of less than 400U. Because life-threatening pulmonary toxic effects can occur, the drug should be discontinued if early signs of pulmonary toxic effects develop. Although decreases in pulmonary function are frequent, they are rarely symptomatic and are reversible after the completion of chemotherapy. Reportedly, men treated curatively for germ cell tumors with cisplatin-based regimens have had elevations in total serum cholesterol.[32] This could not be confirmed, however, in another study.[33]

Radiation therapy, often used in the management of pure seminomatous germ cell cancers, has been linked to the development of secondary cancers, especially solid tumors in the radiation portal, usually after a latency period of a decade or more.[25,34] These include melanoma and cancers of the stomach, bladder, colon, rectum, pancreas, lung, pleura, prostate, kidney, connective tissue, and thyroid. Chemotherapy has also been associated with an elevated risk of secondary cancers.[25]

Oligospermia or sperm abnormalities prior to therapy are common. Radiation therapy, used to treat pure seminomatous testicular cancers, can cause fertility problems because of radiation scatter to the remaining testicle during radiation therapy to retroperitoneal lymph nodes as evidenced in the SWOG-8711 trial, for example.[35] (For more information on fertility, refer to the Sexuality and Reproductive Issues summary.) Depending on scatter dose, sperm counts fall after radiation therapy but may recover over the course of 1 to 2 years. Shielding techniques can be used to decrease the radiation scatter to the remaining normal testicle. As with treatment with chemotherapy, some men have been reported to father children after radiation treatment of seminoma, and the children do not appear to have a high risk of congenital malformations.[20,35][Level of evidence: 3iiiDiv]

Radiation therapy and/or chemotherapy for patients with testicular cancer may be associated with an increase in cardiovascular morbidity. In a retrospective series of 992 patients treated for testicular cancer at the Royal Marsden Hospital between 1982 and 1992, cardiac events were increased approximately 2.5-fold in patients treated with radiation therapy and/or chemotherapy compared with those who underwent surveillance after a median of 10.2 years. The actuarial risks of cardiac events were 7.2% for patients who received radiation therapy (92% of whom did not receive mediastinal radiation therapy), 3.4% for patients who received chemotherapy (primarily platinum-based), 4.1% for patients who received combined therapy, and 1.4% for patients who underwent surveillance management after 10 years of follow-up.[36] A population-based retrospective study of 2,339 testicular cancer survivors in the Netherlands, treated between 1965 and 1995 and followed for a median of 18.4 years, found that the overall incidence of coronary heart disease (i.e., myocardial infarction and/or angina pectoris) was increased 1.17 times (95% confidence interval [CI], 1.04–1.31) compared with the general population.[37] Patients who received radiation therapy to the mediastinum had a 2.5-fold (95% CI, 1.8–3.4) increased risk of coronary heart disease, and those who also received chemotherapy had an almost 3-fold (95% CI, 1.7–4.8) increased risk. Patients who were treated with infradiaphragmatic radiation therapy alone had no significantly increased risk of coronary heart disease. In multivariate Cox regression analyses, the older chemotherapy regimen of cisplatin, vinblastine, and bleomycin (PVB), used until the mid 1980s, was associated with a significant 1.9-fold (95% CI, 1.2–2.9) increased risk of cardiovascular disease (i.e., myocardial infarction, angina pectoris, and heart failure combined). The newer regimen of bleomycin, etoposide, and cisplatin (BEP) was associated with a borderline significant 1.5-fold (95% CI, 1.0–2.2) increased risk of cardiovascular disease.[25,37][Level of evidence: 3iiiDii]

Although testicular cancer is highly curable, all newly diagnosed patients are appropriately considered candidates for clinical trials designed to decrease morbidity of treatment while further improving cure rates.

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Bosl GJ, Bajorin DF, Sheinfeld J, et al.: Cancer of the testis. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1269-90.
3. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 53 (3): 478-96, 2008.
4. Bajorin DF, Bosl GJ: The use of serum tumor markers in the prognosis and treatment of germ cell tumors. Cancer: Principles and Practice of Oncology Updates 6(1): 1-11, 1992.
5. Mead GM, Stenning SP, Parkinson MC, et al.: The Second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumors. Medical Research Council Testicular Tumour Working Party. J Clin Oncol 10 (1): 85-94, 1992.
6. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.
7. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 53 (3): 497-513, 2008.
8. Leibovitch I, Baniel J, Foster RS, et al.: The clinical implications of procedural deviations during orchiectomy for nonseminomatous testis cancer. J Urol 154 (3): 935-9, 1995.
9. Capelouto CC, Clark PE, Ransil BJ, et al.: A review of scrotal violation in testicular cancer: is adjuvant local therapy necessary? J Urol 153 (3 Pt 2): 981-5, 1995.
10. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
11. Gerl A, Clemm C, Schmeller N, et al.: Late relapse of germ cell tumors after cisplatin-based chemotherapy. Ann Oncol 8 (1): 41-7, 1997.
12. Socinski MA, Stomper PC: Radiologic evaluation of nonseminomatous germ cell tumor of the testis. Semin Urol 6 (3): 203-15, 1988.
13. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988.
14. Donohue JP, Thornhill JA, Foster RS, et al.: The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). J Urol 153 (1): 85-9, 1995.
15. Osterlind A, Berthelsen JG, Abildgaard N, et al.: Risk of bilateral testicular germ cell cancer in Denmark: 1960-1984. J Natl Cancer Inst 83 (19): 1391-5, 1991.
16. Colls BM, Harvey VJ, Skelton L, et al.: Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978-1994. J Clin Oncol 14 (7): 2061-5, 1996.
17. Fosså SD, Chen J, Schonfeld SJ, et al.: Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst 97 (14): 1056-66, 2005.
18. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, et al.: Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 11 (3): 415-24, 1993.
19. Foster RS, Donohue JP: Surgical treatment of clinical stage A nonseminomatous testis cancer. Semin Oncol 19 (2): 166-70, 1992.
20. Brydøy M, Fosså SD, Klepp O, et al.: Paternity following treatment for testicular cancer. J Natl Cancer Inst 97 (21): 1580-8, 2005.
21. Drasga RE, Einhorn LH, Williams SD, et al.: Fertility after chemotherapy for testicular cancer. J Clin Oncol 1 (3): 179-83, 1983.
22. Nijman JM, Schraffordt Koops H, Kremer J, et al.: Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors. J Clin Oncol 5 (4): 651-6, 1987.
23. Hansen PV, Trykker H, Helkjoer PE, et al.: Testicular function in patients with testicular cancer treated with orchiectomy alone or orchiectomy plus cisplatin-based chemotherapy. J Natl Cancer Inst 81 (16): 1246-50, 1989.
24. Stephenson WT, Poirier SM, Rubin L, et al.: Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 13 (9): 2278-80, 1995.
25. van den Belt-Dusebout AW, de Wit R, Gietema JA, et al.: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25 (28): 4370-8, 2007.
26. Redman JR, Vugrin D, Arlin ZA, et al.: Leukemia following treatment of germ cell tumors in men. J Clin Oncol 2 (10): 1080-7, 1984.
27. Travis LB, Andersson M, Gospodarowicz M, et al.: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 92 (14): 1165-71, 2000.
28. Pedersen-Bjergaard J, Daugaard G, Hansen SW, et al.: Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet 338 (8763): 359-63, 1991.
29. Nichols CR, Breeden ES, Loehrer PJ, et al.: Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols. J Natl Cancer Inst 85 (1): 36-40, 1993.
30. Bajorin DF, Motzer RJ, Rodriguez E, et al.: Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst 85 (1): 60-2, 1993.
31. Osanto S, Bukman A, Van Hoek F, et al.: Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol 10 (4): 574-9, 1992.
32. Raghavan D, Cox K, Childs A, et al.: Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 10 (9): 1386-9, 1992.
33. Ellis PA, Fitzharris BM, George PM, et al.: Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors. J Clin Oncol 10 (10): 1609-14, 1992.
34. Travis LB, Fosså SD, Schonfeld SJ, et al.: Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97 (18): 1354-65, 2005.
35. Gordon W Jr, Siegmund K, Stanisic TH, et al.: A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group. Int J Radiat Oncol Biol Phys 38 (1): 83-94, 1997.
36. Huddart RA, Norman A, Shahidi M, et al.: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21 (8): 1513-23, 2003.
37. van den Belt-Dusebout AW, Nuver J, de Wit R, et al.: Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24 (3): 467-75, 2006.

Cellular Classification

The following histologic classification of malignant testicular germ cell tumors (testicular cancer) reflects the classification used by the World Health Organization.[1] Less than 50% of malignant testicular germ cell tumors have a single cell type, of which roughly 50% are seminomas. The rest have more than one cell type, and the relative proportions of each cell type should be specified. The cell type of these tumors is important for estimating the risk of metastases and the response to chemotherapy. Polyembryoma presents an unusual growth pattern and is sometimes listed as a single histologic type, though it might better be regarded as a mixed tumor.[1,2,3]

1. Intratubular germ cell neoplasia, unclassified.
2. Malignant pure germ cell tumor (showing a single cell type):
1.Seminoma.
2.Embryonal carcinoma.
3.Teratoma.
4.Choriocarcinoma.
5.Yolk sac tumor.
3. Malignant mixed germ cell tumor (showing more than one histologic pattern):
1.Embryonal carcinoma and teratoma with or without seminoma.
2.Embryonal carcinoma and yolk sac tumor with or without seminoma.
3.Embryonal carcinoma and seminoma.
4.Yolk sac tumor and teratoma with or without seminoma.
5.Choriocarcinoma and any other element.
4. Polyembryoma.

References:

1. Woodward PJ, Heidenreich A, Looijenga LHJ, et al.: Germ cell tumours. In: Eble JN, Sauter G, Epstein JI, et al.: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press, 2004, pp 221-49.
2. Ulbright TM: Testicular and paratesticular tumors. In: Mills SE, ed.: Sternberg's Diagnostic Surgical Pathology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2004, pp 2167-2232.
3. Bosl GJ, Bajorin DF, Sheinfeld J, et al.: Cancer of the testis. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1269-90.

Stage Information

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

TNM Definitions

PRIMARY TUMOR (T)

The extent of primary tumor is classified after radical orchiectomy, and for this reason a pathologic stage is assigned.

  • pTX: Primary tumor cannot be assessed*
  • pT0: No evidence of primary tumor (e.g., histologic scar in testis)
  • pTis: Intratubular germ cell neoplasia (carcinoma)
  • pT1: Tumor limited to the testis and epididymis without lymphatic/vascular invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis
  • pT2: Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
  • pT3: Tumor invades the spermatic cord with or without vascular/lymphatic invasion
  • pT4: Tumor invades the scrotum with or without vascular/lymphatic invasion

*Except for pTis and pT4, the extent of primary tumor is classified by radical orchiectomy. TX may be used for other categories in the absence of radical orchiectomy.

Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis with a single lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, 2 cm or less in greatest dimension
  • N2: Metastasis with a single lymph node mass larger than 2 cm but no more than 5 cm in greatest dimension; or multiple lymph nodes, no more than 5 cm in greatest dimension
  • N3: Metastasis with a lymph node mass 5 cm or more in greatest dimension

Distant metastasis (M)

  • MX: Presence of distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis
    • M1a: Nonregional nodal or pulmonary metastasis
    • M1b: Distant metastasis other than to nonregional lymph nodes and lungs

Serum tumor markers (S)

  • SX: Marker studies not available or not performed
  • S0: Marker study levels within normal limits
  • S1: Lactate dehydrogenase (LDH) less than 1.5 × N*, and
    • Human chorionic gonadotropin (hCG) less than 5,000 (mIU/mL), and
    • Alpha-fetoprotein (AFP) less than 1,000 (ng/mL)
  • S2: LDH 1.5–10 × N* or
    • hCG 5,000–50,000 (mIU/mL), or
    • AFP 1,000–10,000 (ng/mL)
  • S3: LDH more than 10 × N*, or
    • hCG more than 50,000 (mIU/mL), or
    • AFP more than 10,000 (ng/mL)

*N indicates the upper limit of normal for the LDH assay.

AJCC Stage Groupings

Stage 0

  • pTis, N0, M0, S0

Stage I

  • pT1–4, N0, M0, SX

Stage IA

  • pT1, N0, M0, S0

Stage IB

  • pT2, N0, M0, S0
  • pT3, N0, M0, S0
  • pT4, N0, M0, S0

Stage IS

  • Any pT/Tx, N0, M0, S1–3

Stage II

  • Any pT/Tx, N1–3, M0, SX

Stage IIA

  • Any pT/Tx, N1, M0, S0
  • Any pT/Tx, N1, M0, S1

Stage IIB

  • Any pT/Tx, N2, M0, S0
  • Any pT/Tx, N2, M0, S1

Stage IIC

  • Any pT/Tx, N3, M0, S0
  • Any pT/Tx, N3, M0, S1

Stage III

  • Any pT/Tx, any N, M1, SX

Stage IIIA

  • Any pT/Tx, any N, M1a, S0
  • Any pT/Tx, any N, M1a, S1

Stage IIIB

  • Any pT/Tx, N1–3, M0, S2
  • Any pT/Tx, any N, M1a, S2

Stage IIIC

  • Any pT/Tx, N1–3, M0, S3
  • Any pT/Tx, any N, M1a, S3
  • Any pT/Tx, any N, M1b, any S

In addition to the clinical stage definitions, surgical stage may be designated based on the results of surgical removal and microscopic examination of tissue.

STAGE I

Stage I testicular cancer is limited to the testis. Invasion of the scrotal wall by tumor or interruption of the scrotal wall by previous surgery does not change the stage but does increase the risk of spread to the inguinal lymph nodes, and this must be considered in treatment and follow-up. Invasion of the epididymis tunica albuginea and/or the spermatic cord also does not change the stage but does increase the risk of retroperitoneal nodal involvement and the risk of recurrence. This stage corresponds to AJCC stage I and stage II.

STAGE II

Stage II testicular cancer involves the testis and the retroperitoneal or para-aortic lymph nodes usually in the region of the kidney. Retroperitoneal involvement should be further characterized by the number of nodes involved and the size of involved nodes. The risk of recurrence is increased if more than five nodes are involved, if the size of one or more involved nodes is more than 2 cm, or if there is extranodal fat involvement. Bulky stage II disease describes patients with extensive retroperitoneal nodes (>5 cm) who require primary chemotherapy and who have a less favorable prognosis. This stage corresponds to AJCC stage III and stage IV (no distant metastasis).

STAGE III

Stage III implies spread beyond the retroperitoneal nodes based on physical examination, x-rays, and/or blood tests. Stage III is subdivided into nonbulky stage III versus bulky stage III. In nonbulky stage III, metastases are limited to lymph nodes and lung with no mass more than 2 cm in diameter. Bulky stage III includes extensive retroperitoneal nodal involvement, plus lung nodules or spread to other organs such as the liver or brain. This stage corresponds to AJCC stage IV (distant metastasis).

References:

1. Testis. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 317-322.

Treatment Option Overview

Testicular cancer is broadly divided into seminoma and nonseminoma for treatment planning because seminomatous types of testicular cancer are more sensitive to radiation therapy. Nonseminomatous testicular tumors include yolk sac tumors.

An international germ cell tumor prognostic classification has been developed based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous and 660 patients with metastatic seminomatous germ cell tumors.[1] All patients received treatment with cisplatin- or carboplatin-containing therapy as their first chemotherapy course. The prognostic classification, shown below, was agreed on in 1997 by all major clinical trial groups worldwide. It should be used for reporting clinical trial results of patients with germ cell tumors.

A meta-analysis of treatment outcomes for patients with advanced nonseminoma suggested that 5-year survival rates have improved for those patients with a poor prognosis during the period of 1989 to 2004.[2] In addition to improved therapy, the improvement seen in these survival rates could be due to publication bias, changes in patient selection in reported clinical trials, or more sensitive staging methods that could migrate less advanced stages to more advanced stage categories (i.e., stage migration).

Good Prognosis

Nonseminoma:

  • Testis/retroperitoneal primary, and
  • No nonpulmonary visceral metastases, and
  • Good markers–all of:
    • Alpha-fetoprotein (AFP) less than 1,000 ng/mL, and
    • Human chorionic gonadotropin (hCG) less than 5,000 IU/mL (1,000 ng/mL), and
    • Lactate dehydrogenase (LDH) less than 1.5 × the upper limit of normal

    56%–61% of nonseminomas

    5-year progression-free survival (PFS) is 89%; 5-year survival is 92%–94%

Seminoma:

  • Any primary site, and
  • No nonpulmonary visceral metastases, and
  • Normal AFP, any hCG, any LDH

    90% of seminomas

    5-year PFS is 82%; 5-year survival is 86%

Intermediate Prognosis

Nonseminoma:

  • Testis/retroperitoneal primary, and
  • No nonpulmonary visceral metastases, and
  • Intermediate markers–any of:
    • AFP 1,000 or more and 10,000 ng/mL or more, or
    • hCG 5,000 IU/L or more and 50,000 IU/L or more, or
    • LDH 1.5 or more × N* and 10 × N*

    13%–28% of nonseminomas

    5-year PFS is 75%; 5-year survival is 80%–83%

    *N indicates the upper limit of normal for the LDH assay.

Seminoma:

  • Any primary site, and
  • Nonpulmonary visceral metastases, and
  • Normal AFP, any hCG, any LDH

    10% of seminomas

    5-year PFS is 67%; 5-year survival is 72%

Poor Prognosis

Nonseminoma:

  • Mediastinal primary, or
  • Nonpulmonary visceral metastases, or
  • For markers–any of:
    • AFP more than 10,000 ng/mL, or
    • hCG more than 50,000 IU/mL (10,000 ng/mL), or
    • LDH more than 10 × the upper limit of normal

    16%–26% of nonseminomas

    5-year PFS is 41%; 5-year survival is 71%

Seminoma:

  • No patients are classified as poor prognosis.

References:

1. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.
2. van Dijk MR, Steyerberg EW, Habbema JD: Survival of non-seminomatous germ cell cancer patients according to the IGCC classification: An update based on meta-analysis. Eur J Cancer 42 (7): 820-6, 2006.

Stage I Testicular Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage I Seminoma

Stage I seminoma has a cure rate of greater than 95% regardless of whether or not postorchiectomy adjuvant therapy is given.

STANDARD TREATMENT OPTIONS:

1. Radical inguinal orchiectomy with no retroperitoneal node radiation therapy followed by frequent determination of serum markers, chest x-rays, and computed tomographic (CT) scans (surveillance). Results of multiple clinical series, with more than 900 patients with stage I seminoma managed by postorchiectomy surveillance, have been reported.[1,2,3] The overall tumor recurrence rate is 15% to 20%, and nearly all patients whose disease recurred were cured by radiation therapy or chemotherapy. Thus, the overall cure rate is indistinguishable from that achieved with adjuvant radiation therapy. Relapses after 5 years are unusual but can occur,[3]
2. Radical inguinal orchiectomy followed by single-dose carboplatin adjuvant therapy. In a large randomized controlled equivalency trial comparing para-aortic (or dog-leg field, if clinically indicated) radiation to a single dose of carboplatin (concentration-versus-time curve [AUC] × 7) after radical inguinal orchiectomy, relapse-free survival (RFS) and overall survival (OS) rates were equivalent after a median follow-up of 4 years.[4][Level of evidence: 1iiA]
3. Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy. Many radiation therapists recommend prophylactic radiation of the retroperitoneal nodes even with a negative lymphangiogram and/or CT scan because approximately 15% of the patients will have occult nodal spread that can be cured with radiation therapy.[5,6] Relapse rates and toxic effects were studied in a randomized comparison in the MRC-TE08 trial, for example, of para-aortic radiation therapy alone versus para-aortic radiation therapy with an added ipsilateral iliac lymph node field.[7] Three-year RFS rates were virtually identical (96% vs. 96.6%) as were OS rates (99.3% vs. 100%). Pelvic RFS rates were 98.2% versus 100%; the 95% confidence interval (CI) for the difference in pelvic RFS rates was 0% to 3.7%. A statistically significant increase was observed in leukopenia and diarrhea associated with the ipsilateral iliac radiation therapy. Patients with tumors with vascular invasion seem at higher risk for nodal metastases.[8] In a randomized trial (EORTC-30942), radiation to 20 Gy over 10 daily fractions was clinically equivalent to 30 Gy over 15 fractions after a median follow-up of 61 months in both RFS and OS. Patient-reported lethargy and ability to perform normal work were better in the lower-dose regimen.[9][Level of evidence: 1iiA]

Stage I Nonseminoma

Stage I nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, a surgical technique for sparing sympathetic ganglia and chains should be used. This technique is associated with postoperative fertility in most patients and appears to be as effective as non-nerve-sparing procedures in preventing retroperitoneal relapse.[10] Retroperitoneal dissection of lymph nodes is not helpful in the management of children, and potential morbidity of the surgery is not justified by the information obtained.[11]

STANDARD TREATMENT OPTIONS:

1. Removal of the testicle through the groin followed (in adults) by retroperitoneal lymph node dissection (RPLND) . A nerve-sparing RPLND that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPLND dissection.[10,12] Surgery should be followed by monthly determination of serum markers and chest x-rays for the first year and 1- to 2-month determinations for the second year.[13,14] In patients with pathologic stage I disease after RPLND, the presence of lymphatic or venous invasion in the primary tumor appears to predict for relapse.[15] In a large Testicular Cancer Intergroup Study, the relapse rate was 19% in those with vascular invasion versus 6% in those without vascular invasion. Retroperitoneal dissection of lymph nodes is not helpful in the management of children, and potential morbidity of the surgery is not justified by the information obtained.[11] In a large study, 27% of clinical stage I tumors had metastatic involvement of removed lymph nodes and were upstaged to pathological stage II.[16] Chemotherapy is employed immediately on first evidence of recurrence. In a large study, 15% of patients with a negative lymph node dissection experienced recurrence, which was usually pulmonary and usually within 18 months.[16]
2. Radical inguinal orchiectomy with no RPLND followed by regular history (e.g., every 1–2 months), physical examination, determination of serum markers, and, during the first year, abdominal CT scan (surveillance).[2] Intervals for abdominal CT scans have varied from every 2 months to scans at 3 months and 12 months postorchiectomy with apparently similar outcomes .[2,17][Level of evidence: 1iiA] Disease recurrence is rarely detected by chest x-ray alone, so chest x-ray may play little or no role in routine surveillance.[18] Long-term follow-up is important since relapses have been reported more than 5 years after the orchiectomy in patients who did not undergo a retroperitoneal dissection.[19,20,21]

This option should be considered only if:

1. CT scan and serum markers are negative. Lymphangiography, when CT scan and serum markers are negative, does not appear to significantly add to patient management.[22]
2.The patient and physician accept the need for repeat CT scans as necessary to continue the periodic monitoring of the retroperitoneal lymph nodes. Children are adequately followed by serum markers alpha-fetoprotein (AFP), chest x-rays, and clinical examination.[11]
3.The patient will diligently follow a program of regular checkups for 2 years, which includes history, physical examination, x-ray of abdominal lymph nodes, and determination of serum markers.
4.The physician accepts responsibility for seeing that a follow-up schedule is maintained as noted for 2 years and then periodically beyond 2 years.
3. Adjuvant therapy consisting of two courses of cisplatin, bleomycin, and etoposide in patients with clinical stage I disease who are considered at high risk of relapse (about 50% predicted relapse rate based on presence of vascular invasion and histologic type).[23] In 114 such patients, the RFS at 2 years was 98% (lower bound of 95% CI, 95%). Another study of high-risk clinical stage I patients treated with two adjuvant courses of cisplatin, etoposide, and bleomycin has been reported.[24] Relapse rates after chemotherapy are less than 5% compared with about 50% in historical series of high-risk patients followed without adjuvant chemotherapy. In the historical series, however, cure rates have been 95% or more after chemotherapy for relapse. It is unclear which approach is superior in outcome. The adjuvant chemotherapy series is too small to draw conclusions about the risk of chemotherapy-induced secondary malignancies, impact on fertility, or risk of late relapse.

Data suggest that relapse rates are higher in patients with histologic evidence of lymphatic or venous invasion and lower when the primary tumor contains mature teratoma.[25] Some investigators have reported higher relapse rates in patients with embryonal cell histology and recommend RPLND for such patients.[16,26] Other investigators have not found a higher relapse rate for this subgroup.[25,27] Additionally, some investigators recommend RPLND in patients with a normal preorchiectomy AFP [16,26] because they feel the marker cannot be used as an indicator of relapse during follow-up. Since marker-negative patients may be marker-positive at relapse, and marker-positive patients may be marker-negative at relapse, some investigators do not view a negative AFP as a contraindication to a surveillance policy.[27]

A single course of cisplatin, bleomycin, and etoposide has also been given to clinical stage I patients with good results.[28] In a multicenter trial, 382 patients were randomly assigned to chemotherapy versus RPLND. The 2-year recurrence-free rates were 99.5% versus 91.9% (absolute difference 7.6%; 95% confidence interval 3.1% to 12.1%). There were no treatment-related or cancer-specific deaths in either arm of the study.[28][Level of evidence 1iiD]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Gospodarwicz MK, Sturgeon JF, Jewett MA: Early stage and advanced seminoma: role of radiation therapy, surgery, and chemotherapy. Semin Oncol 25 (2): 160-73, 1998.
2. Francis R, Bower M, Brunström G, et al.: Surveillance for stage I testicular germ cell tumours: results and cost benefit analysis of management options. Eur J Cancer 36 (15): 1925-32, 2000.
3. Choo R, Thomas G, Woo T, et al.: Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma. Int J Radiat Oncol Biol Phys 61 (3): 736-40, 2005.
4. Oliver RT, Mason MD, Mead GM, et al.: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 366 (9482): 293-300, 2005 Jul 23-29.
5. Stutzman RE, McLeod DG: Radiation therapy: a primary treatment modality for seminoma. Urol Clin North Am 7 (3): 757-64, 1980.
6. Duchesne GM, Horwich A, Dearnaley DP, et al.: Orchidectomy alone for stage I seminoma of the testis. Cancer 65 (5): 1115-8, 1990.
7. Fosså SD, Horwich A, Russell JM, et al.: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 17 (4): 1146, 1999.
8. Marks LB, Rutgers JL, Shipley WU, et al.: Testicular seminoma: clinical and pathological features that may predict para-aortic lymph node metastases. J Urol 143 (3): 524-7, 1990.
9. Jones WG, Fossa SD, Mead GM, et al.: Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 23 (6): 1200-8, 2005.
10. Foster RS, McNulty A, Rubin LR, et al.: The fertility of patients with clinical stage I testis cancer managed by nerve sparing retroperitoneal lymph node dissection. J Urol 152 (4): 1139-42; discussion 1142-3, 1994.
11. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
12. Foster RS, Donohue JP: Surgical treatment of clinical stage A nonseminomatous testis cancer. Semin Oncol 19 (2): 166-70, 1992.
13. Lange PH, Narayan P, Fraley EE: Fertility issues following therapy for testicular cancer. Semin Urol 2 (4): 264-74, 1984.
14. Williams SD, Einhorn LH: Clinical stage I testis tumors: the medical oncologist's view. Cancer Treat Rep 66 (1): 15-8, 1982.
15. Sesterhenn IA, Weiss RB, Mostofi FK, et al.: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 10 (1): 69-78, 1992.
16. Klepp O, Olsson AM, Henrikson H, et al.: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian Testicular Cancer Group. J Clin Oncol 8 (3): 509-18, 1990.
17. Rustin GJ, Mead GM, Stenning SP, et al.: Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197--the National Cancer Research Institute Testis Cancer Clinical Studies Group. J Clin Oncol 25 (11): 1310-5, 2007.
18. Sharir S, Jewett MA, Sturgeon JF, et al.: Progression detection of stage I nonseminomatous testis cancer on surveillance: implications for the followup protocol. J Urol 161 (2): 472-5; discussion 475-6, 1999.
19. Rørth M, Jacobsen GK, von der Maase H, et al.: Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. Danish Testicular Cancer Study Group. J Clin Oncol 9 (9): 1543-8, 1991.
20. Sujka SK, Huben RP: Clinical stage I nonseminomatous germ cell tumors of testis. Observation vs retroperitoneal lymph node dissection. Urology 38 (1): 29-31, 1991.
21. Sturgeon JF, Jewett MA, Alison RE, et al.: Surveillance after orchidectomy for patients with clinical stage I nonseminomatous testis tumors. J Clin Oncol 10 (4): 564-8, 1992.
22. Wishnow KI, Johnson DE, Tenney D: Are lymphangiograms necessary before placing patients with nonseminomatous testicular tumors on surveillance? J Urol 141 (5): 1133-5, 1989.
23. Cullen MH, Stenning SP, Parkinson MC, et al.: Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 14 (4): 1106-13, 1996.
24. Pont J, Albrecht W, Postner G, et al.: Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol 14 (2): 441-8, 1996.
25. Alexandre J, Fizazi K, Mahé C, et al.: Stage I non-seminomatous germ-cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse. Eur J Cancer 37 (5): 576-82, 2001.
26. Read G, Stenning SP, Cullen MH, et al.: Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol 10 (11): 1762-8, 1992.
27. Colls BM, Harvey VJ, Skelton L, et al.: Results of the surveillance policy of stage I non-seminomatous germ cell testicular tumours. Br J Urol 70 (4): 423-8, 1992.
28. Albers P, Siener R, Krege S, et al.: Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol 26 (18): 2966-72, 2008.

Stage II Testicular Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage II Seminoma

Stage II seminoma is divided into bulky and nonbulky disease for treatment planning and expression of prognosis. Bulky disease is generally defined as tumors larger than 5 cm on a computed tomographic (CT) scan.

Nonbulky stage II disease has a cure rate of more than 90% with radiation alone at doses of 30 Gy to 36 Gy.[1] While earlier studies reported that bulky stage II seminoma had a cure rate of 70% with radiation alone, studies using improved treatment planning and equipment as well as careful selection of patients (including the use of tumor markers) have reported an improvement in the results of radiation therapy in the treatment of patients with bulky stage II seminoma.[2,3] Combination chemotherapy with cisplatin is also effective therapy in patients with bulky stage II seminomas. Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric radiation of residual persistent abnormalities or attempts to resect residual masses 3 cm or larger. Either approach is controversial. In a combined retrospective consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at 10 treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[4][Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number with residual seminoma that require additional therapy.[5] Nevertheless, other reports indicate that the size of the residual mass does not correlate well with active residual disease, most residual masses do not grow, and frequent marker and CT scan evaluation is a viable option even when the residual mass is 3 cm or larger.[6]

STANDARD TREATMENT OPTIONS:

For patients with nonbulky tumors

  • Radical inguinal orchiectomy followed by radiation therapy to the retroperitoneal and ipsilateral pelvic lymph nodes. Evidence favors the omission of prophylactic radiation therapy to the mediastinum and neck.[7,8] Radiation therapy to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk.

For patients with bulky tumors

  • Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen) or by radiation therapy to the abdominal and pelvic lymph nodes.[2,3,9,10,11] Recurrence rate is higher after radiation therapy for bulky stage II tumors than radiation therapy for nonbulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (=5–10 cm).[12] Controversy exists over whether any residual masses present at the completion of chemotherapy should be empirically irradiated, or whether masses larger than 3 cm should be resected.[5,6]

Stage II Nonseminoma

Stage II nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, surgical techniques for sparing sympathetic ganglia and chains without compromising the total removal of all involved nodes are available, though this technique may not be feasible in many patients. This technique is associated with postoperative preservation of ejaculation in a large number of patients.[13,14,15] In most patients, an orchiectomy is performed prior to starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site and chemotherapy has been initiated, subsequent orchiectomy is generally performed, since chemotherapy may not eradicate the primary cancer. Case reports illustrate that viable tumor was found on postchemotherapy orchiectomy despite the complete response of metastatic lesions.[16]

STANDARD TREATMENT OPTIONS:

1. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving retroperitoneal lymph node dissection (RPLND) followed by monthly checkups, which include physical examination, chest x-ray, and serum marker tests (e.g., alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase). This option of surgery and careful follow-up, reserving chemotherapy for relapse, is particularly attractive for patients who have fewer than six positive nodes at retroperitoneal lymph node dissection, none of which are larger than 2 cm in diameter and with no extracapsular lymph node invasion. Such patients appear to have a relapse rate of about 20% to 30% if followed without chemotherapy, and most are curable with standard chemotherapy if they do relapse.[17] Patients whose markers do not return to normal following the removal of retroperitoneal lymph nodes should be treated with chemotherapy.[13,18] Presence of lymphatic or venous invasion also helps to predict which patients may relapse. In a large Testicular Cancer Intergroup Study, the relapse rate after RPLND was 64% in those who had microscopic evidence of vascular invasion in the primary tumor versus 24% in those who did not.[19] In children, surgical resection of retroperitoneal nodes is generally not performed. Patients with clinical stage II disease are given chemotherapy.[20]
2. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by chemotherapy and then monthly checkups. The results of a large study comparing the first treatment option with the second treatment option were published. Two courses of cisplatin-based chemotherapy (either cisplatin, vinblastine, bleomycin [PVB] or vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin [VAB VI]) prevented a relapse in more than 95% of patients. A 49% relapse rate was seen in patients assigned to observation; however, the majority of these patients could be effectively treated. The study concluded that adjuvant therapy will most often prevent relapse in patients treated with optimal surgery, follow-up, and chemotherapy; however, observation with chemotherapy only for relapse will lead to an equivalent cure rate.[21,22]
3. Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups. This option is considered for patients in whom clinical examination, lymphangiogram, or CT scan show retroperitoneal masses that are large enough to cause concern about resectability.

Chemotherapy regimens include:

  • BEP: bleomycin plus etoposide plus cisplatin for three courses.[23] A modified regimen has been used in children.[20]
  • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[11]

A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.[24]

Other regimens that appear to produce similar survival outcomes but are in less common use include:

  • PVB: cisplatin plus vinblastine plus bleomycin.
  • VAB VI: vinblastine plus dactinomycin plus bleomycin plus cyclophosphamide plus cisplatin.[21]
  • VPV: vinblastine plus cisplatin plus etoposide.[25]

In a randomized comparison of PVB versus BEP, equivalent anticancer activity was seen but with less toxic effects with the use of BEP.[23,26]

If these patients do not achieve a complete response on chemotherapy, surgical removal of residual masses should be performed. The timing of such surgery requires clinical judgment but would occur most often after three or four cycles of combination chemotherapy and normalization of serum markers. The probability of finding residual teratoma or carcinoma after chemotherapy may be dependent on the histology of the primary tumor. Patients whose primary tumor contained teratomatous elements have a higher probability of having residual teratoma or carcinoma in the retroperitoneal nodes than do patients whose primary tumor contains only embryonal cancer. One study has reported that irrespective of initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Some investigators think that neither size of the initial tumor nor the degree of shrinkage during therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some to recommend surgery with resection of all residual masses apparent on scans in patients who have normal markers after responding to chemotherapy. Some investigators recommend surgery for patients who have initial masses of 3 cm or larger [27] on a CT scan and after chemotherapy have a normal CT scan. This approach remains controversial, and no evidence is available that such an approach improves survival. The presence of persistent nonseminomatous germ cell malignant elements in the resected specimen is an indication for additional chemotherapy.[28] In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. There is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[29]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

  • In some clinical trials, primary chemotherapy has been administered to patients with small volume retroperitoneal disease in an effort to avoid retroperitoneal node dissections. Although a randomized comparison has not been performed, it appears that primary chemotherapy, when compared with primary retroperitoneal node dissection, may produce similar survival in clinical stage II testicular cancer patients.[30,31]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Classen J, Souchon R, Hehr T, et al.: Radiotherapy for early stages testicular seminoma: patterns of care study in Germany. Radiother Oncol 63 (2): 179-86, 2002.
2. Smalley SR, Evans RG, Richardson RL, et al.: Radiotherapy as initial treatment for bulky stage II testicular seminomas. J Clin Oncol 3 (10): 1333-8, 1985.
3. Friedman EL, Garnick MB, Stomper PC, et al.: Therapeutic guidelines and results in advanced seminoma. J Clin Oncol 3 (10): 1325-32, 1985.
4. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33 (6): 829-35, 1997.
5. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 157 (3): 860-2, 1997.
6. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.
7. Stutzman RE, McLeod DG: Radiation therapy: a primary treatment modality for seminoma. Urol Clin North Am 7 (3): 757-64, 1980.
8. Classen J, Schmidberger H, Meisner C, et al.: Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 21 (6): 1101-6, 2003.
9. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 50 (11): 2289-94, 1982.
10. Loehrer PJ Sr, Birch R, Williams SD, et al.: Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol 5 (8): 1212-20, 1987.
11. Bajorin DF, Geller NL, Weisen SF, et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67 (1): 28-32, 1991.
12. Mason BR, Kearsley JH: Radiotherapy for stage 2 testicular seminoma: the prognostic influence of tumor bulk. J Clin Oncol 6 (12): 1856-62, 1988.
13. Lange PH, Narayan P, Fraley EE: Fertility issues following therapy for testicular cancer. Semin Urol 2 (4): 264-74, 1984.
14. Jewett MA, Kong YS, Goldberg SD, et al.: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 139 (6): 1220-4, 1988.
15. Donohue JP, Foster RS, Rowland RG, et al.: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 144 (2 Pt 1): 287-91; discussion 291-2, 1990.
16. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. J Urol 155 (6): 1938-42, 1996.
17. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 9 (8): 1393-6, 1991.
18. Donohue JP, Einhorn LH, Williams SD: Is adjuvant chemotherapy following retroperitoneal lymph node dissection for nonseminomatous testis cancer necessary? Urol Clin North Am 7 (3): 747-56, 1980.
19. Sesterhenn IA, Weiss RB, Mostofi FK, et al.: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 10 (1): 69-78, 1992.
20. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
21. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4 (10): 1493-9, 1986.
22. Williams SD, Stablein DM, Einhorn LH, et al.: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 317 (23): 1433-8, 1987.
23. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.
24. Loehrer PJ Sr, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 13 (2): 470-6, 1995.
25. Wozniak AJ, Samson MK, Shah NT, et al.: A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study. J Clin Oncol 9 (1): 70-6, 1991.
26. Stoter G, Koopman A, Vendrik CP, et al.: Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin. J Clin Oncol 7 (8): 1099-104, 1989.
27. Toner GC, Panicek DM, Heelan RT, et al.: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 8 (10): 1683-94, 1990.
28. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.
29. Leibovitch I, Little JS Jr, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. J Urol 155 (3): 952-4, 1996.
30. Logothetis CJ, Swanson DA, Dexeus F, et al.: Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients. J Clin Oncol 5 (6): 906-11, 1987.
31. Socinski MA, Garnick MB, Stomper PC, et al.: Stage II nonseminomatous germ cell tumors of the testis: an analysis of treatment options in patients with low volume retroperitoneal disease. J Urol 140 (6): 1437-41, 1988.

Stage III Testicular Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage III Seminoma

Stage III seminoma is usually curable.

STANDARD TREATMENT OPTIONS:

  • Radical inguinal orchiectomy followed by multidrug chemotherapy.[1] In seminoma patients, the residual masses after chemotherapy are often fibrotic, though persistent, discrete (large) masses (=3 cm), which may contain residual seminoma that would require additional therapy.[2] The size of the residual mass reportedly does not correlate well with active residual disease; most residual masses do not grow, and frequent marker and computed tomographic (CT) scan evaluation is a viable option even when the residual mass is 3 cm or larger.[3] In some patients, fertility has returned following the use of bleomycin, etoposide, and cisplatin (BEP).[4] In a randomized trial, treatment with four courses of etoposide plus cisplatin (EP) has shown equal efficacy and less toxic effects than vinblastine, dactinomycin, bleomycin, cyclophosphamide, and cisplatin (VAB VI) in the treatment of good-risk patients.[5]

    Chemotherapy combinations include:

    • BEP: bleomycin plus etoposide plus cisplatin.[6,7] A modified regimen has been used in children.[8]
    • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[5]

    Other regimens that appear to produce similar survival outcomes but are in less common use include:

    • PVB: cisplatin plus vinblastine plus bleomycin.[9,10]
    • VIP: etoposide plus ifosfamide plus cisplatin.

A randomized study comparing four courses of BEP to four courses of VIP showed similar overall survival and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen.

Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric radiation of residual persistent abnormalities or attempts to resect residual masses 3 cm or larger. Either approach is controversial. In a combined retrospective consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[12][Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma that require additional therapy.[2] Nevertheless, other reports indicate that size of the residual mass does not correlate well with active residual disease, most residual masses do not grow, and frequent marker and CT scan evaluation is a viable option even when the residual mass is 3 cm or larger.[3]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

  • Patients are usually eligible for the same chemotherapy clinical trials as those patients with nonseminomatous germ cell tumors.

Stage III Nonseminoma

Stage III nonseminoma is usually curable (70%) with standard chemotherapy. In some patients fertility has returned following the use of chemotherapy. The 30% of patients who are not cured with standard chemotherapy usually have widespread visceral metastases, high tumor markers, or mediastinal primary tumors at presentation. In most patients, an orchiectomy is performed prior to starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site and chemotherapy has been initiated, subsequent orchiectomy is generally performed because chemotherapy may not eradicate the primary cancer. Case reports illustrate that viable tumor was found on postchemotherapy orchiectomy despite complete response of metastatic lesions.[13]

Some retrospective data suggest that the experience of the treating institution may impact the outcome of patients with stage III nonseminoma. Data from 380 patients treated from 1990 to 1994 on the same study protocol at 49 institutions in the European Organization for Research and Treatment of Cancer and the Medical Research Council were analyzed.[14] Overall 2-year survival for the 55 patients treated at institutions that entered fewer than 5 patients onto the protocol was 62% (95% confidence interval [CI], 48%–75%) versus 77% (95% CI, 72%–81%) in the institutions that entered 5 or more patients onto the protocol. As in any nonrandomized study design, patient selection factors and factors leading patients to choose treatment at one center over another can make interpretation of results difficult.

The results of a large cooperative group randomized study of PVB versus BEP have been reported.[6] The BEP regimen produced less neuromuscular toxic effects and was more effective in patients with advanced disease, which makes it the preferable regimen of these two combinations. In addition, three courses of BEP have been shown to be equivalent to four courses in patients with minimal or moderate extent of disseminated germ cell tumors.[7] A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.[15] Although another randomized study in good-prognosis patients treated with four courses of cisplatin plus vinblastine with or without bleomycin (PV with or without B) has shown better tumor-specific survival with PVB, this was offset by more toxic deaths. OS rates were not significantly different between four courses of PV versus PVB.[16]

In patients with poor-risk germ cell tumors, the standard-dose cisplatin regimen has been shown to be the equivalent of high-dose cisplatin in terms of complete response, cure rates, and survival; moreover, patients in the high-dose cisplatin regimen experienced significantly more toxic effects.[17]

Many patients with poor-risk nonseminomatous testicular germ cell tumors who have a serum beta human chorionic gonadotropin (ßhCG) level higher than 50,000 IU/mL at the initiation of cisplatin-based therapy (BEP or PVB) will still have an elevated ßhCG level at the completion of therapy, showing an initial rapid decrease in ßhCG followed by a plateau.[18] In the absence of other signs of progressing disease, monthly evaluation with initiation of salvage therapy if and when there is serologic progression may be appropriate. Many patients, however, will remain disease-free without further therapy.[18][Level of evidence: 3iiDiv]

Patients who present with brain metastases should be treated with chemotherapy and simultaneous whole brain radiation therapy (50 Gy/25 fractions).[19]

STANDARD TREATMENT OPTIONS:

1. Chemotherapy:
  • BEP: bleomycin plus etoposide plus cisplatin.[6,7] A modified regimen has been used in children.[8]
  • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[5]

Other regimens that appear to produce similar survival outcomes but have been studied less extensively or are in less common use include:

  • PVB: cisplatin plus vinblastine plus bleomycin.[20]
  • POMB/ACE: platinum plus vincristine plus methotrexate plus bleomycin plus dactinomycin plus cyclophosphamide plus etoposide.[21]
  • VIP: etoposide plus ifosfamide plus cisplatin.

A randomized study comparing four courses of BEP to four courses of VIP showed similar OS and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen.

2. In selected cases surgery should be used after chemotherapy to remove residual masses to determine if viable tumor cells remain, since such a finding is an indication for further chemotherapy. Surgical removal of residual masses is also necessary to prevent regrowth of teratomas and growth of nongerm cell elements present in some of these masses.[22,23]

A study has reported that regardless of initial histology, a significant risk exists of teratoma or carcinoma in residual masses after chemotherapy. Neither size of the initial tumor nor degree of shrinkage during therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some to recommend surgery with resection of all residual masses apparent on scans in patients who have normal markers after responding to chemotherapy.[24]

Some patients may have discordant pathologic findings (e.g., fibrosis/necrosis, teratoma, or carcinoma) in residual masses in the abdomen versus the chest. Some medical centers perform simultaneous retroperitoneal and thoracic operations to remove residual masses [3,25] but most do not. Although the agreement among the histologies of residual masses found after chemotherapy above versus below the diaphragm is only moderate (kappa statistic = 0.42), some evidence exists that if retroperitoneal resection is performed first, results can be used to guide decisions about whether to perform a thoracotomy.[26] In a multi-institutional case series of surgery to remove postchemotherapy residual masses in 159 patients, necrosis only was found at thoracotomy in about 90% of patients who had necrosis only in their retroperitoneal masses. The figure was about 95% if the original testicular primary tumor had contained no teratomatous elements. Conversely, the histology of residual masses at thoracotomy did not predict nearly as well the histology of retroperitoneal masses.[26]

Even patients who have initial masses of 3 cm or larger on CT scan and who, after chemotherapy have normal CT scan and markers, may have residual teratoma or carcinoma. This approach remains controversial, and no evidence exists that such an approach improves survival. The presence of persistent malignant elements in the resected specimen is an indication for additional chemotherapy.[27] In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. A physiologic blood-testis barrier seems to appear, and there is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[28] Some investigators have suggested that in children, 90% of whom have yolk sac tumors, radiation therapy should be given to residual masses after chemotherapy rather than surgery.[8]

Patients who relapse with brain metastases after a complete initial response to chemotherapy require further chemotherapy, with simultaneous whole-brain radiation therapy, and consideration of surgical excision of solitary lesions.[19]

TREATMENT OPTIONS UNDER CLINICAL EVALUATION:

1. Clinical trials.
2. High-dose chemotherapy with autologous bone marrow transplantation in selected patients with bulky disease such as in the MSKCC-94076 trial.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 50 (11): 2289-94, 1982.
2. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 157 (3): 860-2, 1997.
3. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.
4. Drasga RE, Einhorn LH, Williams SD, et al.: Fertility after chemotherapy for testicular cancer. J Clin Oncol 1 (3): 179-83, 1983.
5. Bajorin DF, Geller NL, Weisen SF, et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67 (1): 28-32, 1991.
6. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.
7. Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989.
8. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
9. Einhorn LH, Williams SD: Chemotherapy of disseminated seminoma. Cancer Clin Trials 3 (4): 307-13, 1980.
10. Loehrer PJ Sr, Birch R, Williams SD, et al.: Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol 5 (8): 1212-20, 1987.
11. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97 (8): 1869-75, 2003.
12. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33 (6): 829-35, 1997.
13. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. J Urol 155 (6): 1938-42, 1996.
14. Collette L, Sylvester RJ, Stenning SP, et al.: Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 91 (10): 839-46, 1999.
15. Loehrer PJ Sr, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 13 (2): 470-6, 1995.
16. Levi JA, Raghavan D, Harvey V, et al.: The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J Clin Oncol 11 (7): 1300-5, 1993.
17. Nichols CR, Williams SD, Loehrer PJ, et al.: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9 (7): 1163-72, 1991.
18. Zon RT, Nichols C, Einhorn LH: Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels. J Clin Oncol 16 (4): 1294-7, 1998.
19. Spears WT, Morphis JG 2nd, Lester SG, et al.: Brain metastases and testicular tumors: long-term survival. Int J Radiat Oncol Biol Phys 22 (1): 17-22, 1992.
20. Einhorn LH, Williams SD: Chemotherapy of disseminated testicular cancer. A random prospective study. Cancer 46 (6): 1339-44, 1980.
21. Newlands ES, Bagshawe KD, Begent RH, et al.: Current optimum management of anaplastic germ cell tumours of the testis and other sites. Br J Urol 58 (3): 307-14, 1986.
22. Einhorn LH, Williams SD, Mandelbaum I, et al.: Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer 48 (4): 904-8, 1981.
23. Loehrer PJ Sr, Hui S, Clark S, et al.: Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. J Urol 135 (6): 1183-9, 1986.
24. Toner GC, Panicek DM, Heelan RT, et al.: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 8 (10): 1683-94, 1990.
25. Brenner PC, Herr HW, Morse MJ, et al.: Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis. J Clin Oncol 14 (6): 1765-9, 1996.
26. Steyerberg EW, Donohue JP, Gerl A, et al.: Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group. J Urol 158 (2): 474-8, 1997.
27. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.
28. Leibovitch I, Little JS Jr, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. J Urol 155 (3): 952-4, 1996.

Recurrent Testicular Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, site of recurrence, and individual patient considerations. Salvage regimens consisting of ifosfamide, cisplatin, and either etoposide or vinblastine can induce long-term complete responses in about 25% of patients with disease that has persisted or recurred following other cisplatin-based regimens. Patients who have had an initial complete response to first-line chemotherapy and those without extensive disease have the most favorable outcomes.[1,2] This regimen is now the standard initial salvage regimen.[2,3] Few, if any, patients with recurrent nonseminomatous germ cell tumors of extragonadal origin, however, achieve long-term disease-free survival (DFS) using vinblastine, ifosfamide, and cisplatin if their disease recurred after they received an initial regimen containing etoposide and cisplatin.[2][Level of evidence: 3iiDii] High-dose chemotherapy with autologous marrow transplantation has also been used in uncontrolled case series in the setting of recurrent disease.[4,5,6,7,8,9,10,11] However, a randomized controlled trial comparing conventional doses of salvage chemotherapy with high-dose chemotherapy with autologous marrow rescue showed more toxic effects and treatment-related deaths in the high-dose arm without any improvement in response rate or overall survival.[12][Level of evidence: 1iiA] In some highly selected patients with chemorefractory disease confined to a single site, surgical resection may yield long-term DFS.[13,14] One case series suggests that a maintenance regimen of daily oral etoposide (taken 21 days out of 28 days) may benefit patients who achieve a complete remission after salvage therapy.[15]

A special case of late relapse may include patients who relapse more than 2 years after achieving complete remission; this population represents less than 5% of patients who are in complete remission after 2 years. Results with chemotherapy are poor in this patient subset, and surgical treatment appears to be superior, if technically feasible.[16] Teratoma may be amenable to surgery at relapse, and teratoma also has a better prognosis than carcinoma after late relapse. Teratoma is a relatively resistant histologic subtype, so chemotherapy may not be appropriate.

Clinical trials are appropriate and should be considered whenever possible, including phase I and phase II studies for those patients who do not achieve a complete remission with induction therapy, or who do not achieve a complete remission following etoposide and cisplatin for their initial relapse, or for patients who have a second relapse.[17]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Loehrer PJ Sr, Lauer R, Roth BJ, et al.: Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109 (7): 540-6, 1988.
2. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.
3. Motzer RJ, Cooper K, Geller NL, et al.: The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors. Cancer 66 (12): 2476-81, 1990.
4. Broun ER, Nichols CR, Kneebone P, et al.: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117 (2): 124-8, 1992.
5. Droz JP, Pico JL, Ghosn M, et al.: Long-term survivors after salvage high dose chemotherapy with bone marrow rescue in refractory germ cell cancer. Eur J Cancer 27 (7): 831-5, 1991.
6. Cullen MH: Dose-response relationships in testicular cancer. Eur J Cancer 27 (7): 817-8, 1991.
7. Motzer RJ, Mazumdar M, Bosl GJ, et al.: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14 (4): 1098-105, 1996.
8. Motzer RJ, Bosl GJ: High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst 84 (22): 1703-9, 1992.
9. Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000.
10. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.
11. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007.
12. Pico JL, Rosti G, Kramar A, et al.: A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 16 (7): 1152-9, 2005.
13. Murphy BR, Breeden ES, Donohue JP, et al.: Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 11 (2): 324-9, 1993.
14. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.
15. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 13 (5): 1167-9, 1995.
16. Baniel J, Foster RS, Gonin R, et al.: Late relapse of testicular cancer. J Clin Oncol 13 (5): 1170-6, 1995.
17. Motzer RJ, Geller NL, Tan CC, et al.: Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer 67 (5): 1305-10, 1991.

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